Project Summary The Cancer Therapeutics Program has been continuously approved by the NCI CCSG since 1993. The Program seeks to improve patient outcomes through the rapid development of novel research ideas which are translatable to the clinical arena and ideally can be individualized to disease and patient-specific settings. The Programmatic goals are as follows: 1) Bring forward novel preclinical breakthroughs from the bench to the bedside and bring relevant cancer therapeutics from the clinic to the lab in order to enhance the mechanistic understanding of cancer therapeutics; 2) Take new drugs from first-in-human Phase I trials to disease-specific clinical trials that will have a significant impact on establishing new standards of care; and 3) Develop pharmacodynamic and predictive markers to select the best drugs for the patients most likely to respond. These goals are applied across four research themes: targeted therapies, combinations to overcome resistance, immunotherapy, and predictive and pharmacodynamic biomarkers. This Program, which was rated as ?Excellent? at the time of the prior CCSG renewal application, is led by Program Co-Leaders Drs. Ravi Amaravadi and Naomi Haas, who were jointly appointed in September 2013. They succeed Drs. Peter O'Dwyer and Corey Langer, who were asked to become leaders of new cross-Programmatic translational research Initiatives in pancreatic and lung cancer, respectively. The new Co-Leaders were chosen because they have complementary skill sets that match the future directions of the Program. Dr. Amaravadi has expertise in the preclinical-to-translational space, and Dr. Haas has expertise in taking Phase I studies into disease-specific studies and developing multi-institution clinical trials. Drs. Amaravadi and Haas are NCI- funded researchers who bring their scientific vision, innovativeness and energy to this Program, which includes an emphasis on basic and translational research. The 25 Program members represent 10 departments in the Perelman School of Medicine. During the current project period, translational research has continued to be a major focus. Members currently have $6.7M in annual research grant funding (direct costs), of which $3.6M is peer-reviewed and $2.4M is NCI-funded. There have been a total of 361 cancer-related publications authored by Program members during the project period. Of these, 12% are intra-Programmatic, 39% are inter- Programmatic and 57% are multi-institutional.